Hyperferritinemia cataract syndrome (HCS) is a recently discovered genetic disease defined by elevated serum ferritin and cataracts. Dysregulation of L ferritin gene expression is the basis of this human disorder. Specifically, mutations in a discrete regulatory region of the L ferritin gene, the iron' response element, lead to over production of wild type L ferritin protein. Although ferritin is found at high levels in all tissues and extracellular fluids examined to date, cataracts are the only proven pathologic consequence of this constitutive over expression of ferritin. The mechanism of cataract formation in hyperferritinemia cataract syndrome (HCS) is unknown. Understanding the pathobiology of cataractogenesis in HCS is essential to design a rational approach to cataract prevention and treatment. The objective 9f this proposal is to determine the mechanism of HCS cataractogenesis with a long term goal of developing effective preventive and/or therapeutic strategies for these cataracts. The mechanism of cataract formation in HCS will likely have broader implications for cataract formation in general. The specific aims of this proposal all involve investigation of ferritin in eye. First, the normal expression of ferritin in lens and lens cell lines will be determined. Second, over expression of L ferritin in human cell lines and in mouse will be generated as models of HCS. Third, quantitative expression and distribution of L ferritin in HCS lens material will be determined. An animal model that reproduces cataract promises opportunity to 1investigate cataract formation as a function of the interaction of HCS genotype with environmental factors including iron, antioxidants and UV light. This proposal describes a 4 year training program in which the applicant will acquire the requisite experience to become an independent clinician scientist. The sponsor and collaborator's extensive experience in clinical ophthalmology, eye histopathology, genetic cataract and mouse genetics will complement the applicant's prior training in molecular biology, internal medicine and clinical genetics. A strong ophthalmology research program will provide the requisite environment in which to transition the applicant to being an independent physician/researcher in genetics and eye disease.